FDA 'Fast Tracks' Arfolitixorin for Metastatic Colorectal Cancer


After 40 years, a novel agent may be on the fast track to becoming the first drug to improve the standard of care for patients with metastatic colorectal cancer.

The FDA has granted fast track designation to arfolitixorin, stabilized and biologically active pure form of folate, for treatment of patients with metastatic colorectal cancer (mCRC), announced Isofol Medical AB, in a press release.1

Fast track status was granted based on the drug’s potential to fill an unmet medical need for more effective therapies to treat patients with mCRC. The agent may be more attractive than other folates because multi-step metabolic activation is not required with arfolitixorin.2 The agent in under clinical investigation in the phase 3 AGENT study (NCT03750786).3

“We are thrilled that the FDA has granted Fast Track Designation to our lead candidate arfolitixorin. This serves as a strong external validation of arfolitixorin's potential to benefit patients with this devastating disease. Our next clinical milestone is reaching 300 progression-free survival events in the phase 2 AGENT study which means that data can be deblinded so that we can analyze and present top-line results in the first half of 2022,” said Ulf Jungnelius, chief executive officer of Isofol Medical AB, in a press release.1

AGENT is multicenter, randomized, parallel-group, phase 3 of approximately 440 patients with mCRC. The study is being conducted across about 100 sites in Australia, Austria, Canada, France, Germany, Greece, Japan, Spain, Sweden, and the United States.

The goal of the study is to compare the efficacy of arfolitixorin with leucovorin combined with 5-fluorouracil (5-FU), oxaliplatin, and bevacizumab (Avastin) according to modified FOLFOX-6. Patients enrolled in the study are randomized 1:1. Treatment is continued until disease progression and evaluated per RECIST v1.1 criteria.2,3

The primary end point of the AGENT study is objective response rate, and the secondary end points are progression-free survival and duration of response. In addition to these end points, investigators will assess several folate metabolism-related genes as well as transportation-related genes including ATP-binding cassette C3 transporter, methylenetetrahydrofolate dehydrogenase 2, proton-coupled folate transporter, and serine hydroxymethyltransferase 1 to determine how they correlate with treatment outcomes.

The study includes patients with colorectal adenocarcinoma verified by biopsy who have available tumor tissue at screening. Planned first-line therapy for patients enrolled must be 5-FU, oxaliplatin, and bevacizumab. Patients are also required to have at least 1 measurable lesion, a life expectancy of at least 4 months, an ECOG performance status of 0 or 1, adequate baseline laboratory values, be 18 years of age or older, and be taking contraception if female.

Individuals excluded from the study are those with malignancies other than mCRC, who received their last anti-cancer therapy within 6 months, showed progressive disease within 6 months after completion of prior anti-cancer treatment, have Indication for any mCRC (mCRC) surgery or anti- treatment other than study treatment,and those who were previously treated with arfolitixorin. Comorbidities like central nervous system involvement, dihydropyrimidine dehydrogenase deficiency, unresolved bowel obstruction, uncontrolled Crohn's disease, or ulcerative colitis, cardiac disease, and others also made select patients ineligible to enroll in the AGENT study.

The study is ongoing in 94 treatment locations but is not currently recruiting patients with mCRC.

“The fast track designation will enable us to engage more frequently with the FDA to optimally plan for the continued development of arfolitixorin and potentially make it the first novel drug to improve the standard of care in mCRC in over 40 years,” Jungnelius stated in a press release.1


1. Isofol Medical AB (publ) receives fda fast track designation for arfolitixorin in advanced colorectal cancer (mCRC). News release. Isofol Medical AB. November 23, 2021. Accessed November 29, 2021. https://bit.ly/3o0lUpc

2. Lenz HJ, Gibbs P, Stintzing S, et al. AGENT: An open-label phase III study of arfolitixorin versus leucovorin in modified FOLFOX-6 for first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2021;38(4). doi: 10.1200/JCO.2020.38.4_suppl.TPS268

3. A study to compare the efficacy of arfolitixorin versus leucovorin in combination with 5 fluorouracil, oxaliplatin, and bevacizumab in patients with advanced colorectal cancer (AGENT). Clinicaltrials.gov. Accessed November 29, 2021.

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